Severe craniosynostosis with Noonan syndrome phenotype associated with SHOC2 mutation: Clinical evidence of crosslink between FGFR and RAS signaling pathways

Abstract

Dysregulation in the RAS signaling cascade results in a family of malformation syndromes called RASopathies. Meanwhile, alterations in FGFR signaling cascade are responsible for various syndromic forms of craniosynostosis. In general, the phenotypic spectra of RASopathies and craniosynostosis syndromes do not overlap. Recently, however, mutations in ERF, a downstream molecule of the RAS signaling cascade, have been identified as a cause of complex craniosynostosis, suggesting that the RAS and FGFR signaling pathways can interact in the pathogenesis of malformation syndromes. Here, we document a boy with short stature, developmental delay, and severe craniosynostosis involving right coronal, bilateral lambdoid, and sagittal sutures with a de novo mutation in exon1 of SHOC2 (c.4A>G p.Ser2Gly). This observation further supports the existence of a crosslink between the RAS signaling cascade and craniosynostosis. In retrospect, the propositus had physical features suggestive of a dysregulated RAS signaling cascade, such as fetal pleural effusion, fetal hydrops, and atrial tachycardia. In addition to an abnormal cranial shape, which has been reported for this specific mutation, craniosynostosis might be a novel associated phenotype. In conclusion, the phenotypic combination of severe craniosynostosis and RASopathy features observed in the propositus suggests an interaction between the RAS and FGFR signaling cascades. Patients with craniosynostosis in combination with any RASopathy feature may require mutation screening for molecules in the FGFR-RAS signaling cascade.

Cleft palate and hypopituitarism in a patient with Noonan‐like syndrome with loose anagen hair‐1

“…Individuals with NSLH1 are more likely to have intellectual disability, relative macrocephaly, sparse/loose anagen hair, and growth hormone deficiency (GHD) compared to individuals with Noonan syndrome (NS) caused by mutations in other genes. The clinical features of 84 patients with NSLH1 have been described (Table ) (Bader‐Meunier et al, ; Capalbo, Melis, et al, ; Capalbo, Scala, et al, ; Choi et al, ; Cordeddu et al, ; Ekvall, Hagenäs, Allanson, Annerén, & Bondeson, ; Ferrero et al, ; Garavelli et al, ; Gargano et al, ; Gripp et al, ; Hoban, Roberts, Demmer, Jethva, & Shephard, ; Kane et al, ; Komatsuzaki et al, ; Lo, Wang, Wong, & Lee, ; Mazzanti et al, ; Mazzanti et al, ; Şimşek‐Kiper et al, ; Tafazoli, Eshraghi, Koleti, & Abbaszadegan, ; Takenouchi et al, ; Tartaglia, Zampino, & Gelb, ; Tosti et al, ; Tosti et al, ; Tosti & Piraccini, ; Zmolikova et al, ). With the possible exception of one patient with unusual but not well‐defined palatal anatomy (Kumar, Chandar, Koduri, & Sankireddy, ), posterior cleft palate (CP) has not been reported in individuals with NS or with NSLH (Cao, Alrejaye, Klein, Goodwin, & Oberoi, ; Mallineni, Yung Yiu, & King, ).…”

Noonan syndrome with multiple lentigines and associated craniosynostosis

“…Although other RASopathies have rarely been associated with craniosynostoses, this is the first case, to our knowledge, of an association with NSML. This association of craniosynostosis with RAS pathway mutations has been postulated to be due to a downstream signalling interaction of the RAS and FGFR pathways.…”

Genetic Causes of Craniosynostosis: An Update

“…Previously, mutations in KRAS have been identified in patients with Noonan syndrome (OMIM 613706) and craniosynostosis [Takenouchi et al, 2014;Addissie et al, 2015]. Ueda et al [2017] presented more patients with RASopathies and craniosynostosis.…”

“…They identified mutations in PTPN11 in 3 unrelated patients with Noonan syndrome and sagittal synostosis and mutations in BRAF in 4 patients with cardiofaciocutaneous syndrome (all 4 had sagittal and/or lambdoid synostosis) [Ueda et al, 2017]. The exact etiology remains unclear; however, there might be a possible interaction between FGFR and the RAS/MAPK signaling pathways [Takenouchi et al, 2014;Addissie et al, 2015].…”